The present invention relates to a pharmaceutical composition comprising an insulin sensitivity enhancer in combination with one or more other antidiabetics differing from said enhancer in the mechanism of action.
Recent years, the pathology of diabetes has become more and more understood and, in parallel, drugs specific for the respective pathologic states have been developed. Accordingly a variety of drugs having new mechanisms of action have appeared one after another.
Insulin sensitivity enhancers are also known as insulin resistance deblockers because they have the action to normalize the impaired insulin receptor function, and are gathering much attention in these years.
Regarding such insulin sensitivity enhancers, a very useful compound such as pioglitazone has been developed [Fujita et al., Diabetes, 32, 804-810, 1983, JP-A S55(1980)-22636 (EP-A 8203), JP-A S61(1986)-267580 (EP-A 193256)]. Pioglitazone restores the impaired insulin receptor function to normalize the uneven distribution of glucose transporters in cells, the cardinal enzyme systems associated with glycometabolism, such as glucokinase, and enzyme systems associated with lipidmetabolism, such as lipoprotein lipase. As the results, insulin resistance are deblocked to improve glucose tolerance, and lower the plasma concentrations of neutral lipids and free fatty acids. Since these actions of pioglitazone are comparatively gradual and the risk of side effect in long-term administration is also low, this compound is useful for obese patients who are presumed to be highly insulin-resistant.
Also, insulin sensitivity enhancers such as CS-045, thazolidinedione derivatives and substituted thiazolidinedione derivatives are reported to be used in combination with insulin [JP-A H4(1992)-66579, JP-A H4(1992)-69383, JP-A H5(1993)-202042]. However, the pharmaceutical composition having a specific combination of the present invention is unknown.
Diabetes is a chronic disease with diverse pathologic manifestations and is accompanied by lipidmetabolism disorders and circulatory disorders as well as glycometabolism disorders. As the results, diabetes tends to progress entailing various complications in many cases. Therefore, it is necessary to select the drug of choice for the prevailing disease state in each individual case. However, this selection is often difficult in clinical settings because single use of each individual drug can not bring sufficient effects in some disease states and there are various problems such as side effect which is caused by an increased dose or a long-term administration.
In view of the above state of the art, the inventors of the present invention did much research to develop antidiabetics which would not virtually cause adverse reactions even on long-term administration and could be effective for a large cohort of the diabetic population. As a consequence, they discovered that the above object can be accomplished by using an insulin sensitivity enhancer, such as the drug described above, in combination with other antidiabetics differing from said enhancer in the mechanism of action, and accordingly have perfected the present invention.
The present invention, therefore, relates to:
1) Pharmaceutical composition which comprises an insulin sensitivity enhancer in combination with at least one member of the group consisting of an xcex1-glucosidase inhibitor, an aldose reductase inhibitor, a biguanide, a statin compound, a squalene synthesis inhibitor, a fibrate compound, a LDL catabolism enhancer and an angiotensin converting enzyme inhibitor;
2) Pharmaceutical composition according to 1), wherein the insulin sensitivity enhancer is a compound represented by the formula: 
xe2x80x83wherein R represents an optionally substituted hydrocarbon or heterocyclic group; Y represents a group represented by xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR3xe2x80x94 (wherein R3 represents an optionally substituted alkyl group); m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or a C1-7 divalent aliphatic hydrocarbon group; Q represents oxygen atom or sulfur atom; R1 represents hydrogen atom or an alkyl group; ring E may optionally have 1 to 4 substituents, and the substituents may optionally be combined with R1 to form a ring; L and M respectively represent hydrogen atom, or L and M may optionally be combined with each other to form a bond; or a pharmacologically acceptable salt thereof;
3) Pharmaceutical composition according to 2), wherein the compound represented by the formula, (I) is pioglitazone;
4) Pharmaceutical composition according to 1), which comprises an insulin sensitivity enhancer in combination with an xcex1-glucosidase inhibitor;
5) Pharmaceutical composition according to 4), wherein the xcex1-glucosidase inhibitor is voglibose;
6) Pharmaceutical composition according to 4), wherein the insulin sensitivity enhancer is pioglitazone and the xcex1-glucosidase inhibitor is voglibose;
7) Pharmaceutical composition according to 1), which is for prophylaxis or treatment of diabetes;
8) Pharmaceutical composition which comprises a compound represented by the formula: 
xe2x80x83wherein Rxe2x80x2 represents an optionally substituted hydrocarbon or heterocyclic group; Y represents a group represented by xe2x80x94COxe2x80x94, xe2x80x94CH(OH)xe2x80x94 or xe2x80x94NR3xe2x80x94 (wherein R3 represents an optionally substituted alkyl group); m is 0 or 1; n is 0, 1 or 2; X represents CH or N; A represents a bond or a C1-7 divalent aliphatic hydrocarbon group; Q represents oxygen atom or sulfur atom; R1 represents hydrogen atom or an alkyl group; ring E may optionally have 1 to 4 substituents, and the substituents may optionally be combined with R1 to form a ring; L and M respectively represent hydrogen atom, or L and M may optionally be combined with each other to form a bond; with a proviso that Rxe2x80x2 does not represent benzopyranyl group when m and n are O, X represents CH, A represents a bond, Q represents sulfur atom, R1, L and M represent hydrogen atom and ring E does not have further substituents; or a pharmacologically acceptable salt thereof in combination with an insulin secretion enhancer and/or an insulin preparation;
9) Pharmaceutical composition according to 8), wherein the compound represented by the formula (II) is the compound represented by the formula: 
10) Pharmaceutical composition according to 8), wherein the compound represented by the formula (II) is pioglitazone;
11) Pharmaceutical composition according to 8), wherein the insulin secretion enhancer is glibenclamide;
12) Pharmaceutical composition according to 8), wherein the compound represented by the formula (II) is pioglitazone and the insulin secretion enhancer is glibenclamide;
13) Pharmaceutical composition according to 8), which is for prophylaxis or treatment of diabetes.